Prevalence of Cerebrotendinous Xanthomatosis among Patients Diagnosed with Acquired Juvenile-Onset Idiopathic Bilateral Cataracts

Sharon F. Freedman, Charlotte Brennand, John Chiang, Andrea Debarber, Monte A. Del Monte, P. Barton Duell, John Fiorito, Randall Marshall

Research output: Contribution to journalArticle

Abstract

Importance: Cerebrotendinous xanthomatosis (CTX) is a rare autosomal recessive bile acid synthesis disorder caused by mutations in CYP27A1, the gene encoding sterol 27-hydroxylase, which results in elevated levels of plasma cholestanol and urinary bile alcohols. Clinical symptoms and signs may include early-onset chronic diarrhea, juvenile-onset bilateral cataracts, cholestatic jaundice, tendon xanthomas, and progressive neurological deterioration. Although initiation of treatment at a young age can prevent disease complications, diagnosis often occurs after the onset of permanent neurologic damage. Strategies are needed to facilitate early diagnosis. Objective: To evaluate the prevalence of CTX in a patient population diagnosed with early-onset idiopathic bilateral cataracts. Design, Setting, and Participants: This interim analysis of the Cerebrotendinous Xanthomatosis Prevalence Study was conducted in 26 active US sites from November 2015 to June 2017. The study included patients diagnosed as having idiopathic bilateral cataracts from ages 2 to 21 years. Potentially eligible study participants were identified through retrospective medical record review or on receiving care for cataracts at an active site. Data were analyzed from July 2017 to October 2018. Main Outcomes and Measures: Measurement of plasma cholestanol levels and optional urine bile alcohol screening were performed. A plasma cholestanol concentration of 0.4 mg/dL or greater or a positive urine bile alcohol result prompted CYP27A1 genetic testing to confirm the diagnosis of CTX. Results: Of 170 tested patients, 88 (51.8%) were male, and the median (range) age was 10 (2-49) years. A total of 3 patients (1.8%) had biochemical and genetic confirmation of newly diagnosed CTX (plasma cholestanol level greater than 1.0 mg/dL, positive urine bile alcohol result, and disease-causative mutations in CYP27A1). The mean (range) age at cataract diagnosis for patients with CTX was 12 (8-16) years. Reported symptoms included abnormal gait or balance (n = 3), learning disability (n = 2), cognitive decline (n = 2), seizures (n = 2), frequent bone fractures (n = 2), and chronic diarrhea (n = 1). Conclusions and Relevance: To date, 1.8% of patients in this study were diagnosed as having CTX, which is approximately 500-fold the currently estimated prevalence of CTX in the general population (3 to 5 per 100000). These data suggest that juvenile-onset idiopathic bilateral cataracts may be useful as a screening marker for CTX and that ophthalmologists can play an important role in facilitating early identification of this condition..

Original languageEnglish (US)
JournalJAMA ophthalmology
DOIs
StateAccepted/In press - Jan 1 2019

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Cerebrotendinous Xanthomatosis
Cataract
Cholestanols
Cholestanol
Urine
Diarrhea
Catalytic Domain
Cholestanetriol 26-Monooxygenase
Xanthomatosis
Mutation
Obstructive Jaundice
Learning Disorders
Bone Fractures
Genetic Testing
Bile Acids and Salts
Gait
Tendons
Nervous System
Population
Signs and Symptoms

ASJC Scopus subject areas

  • Ophthalmology

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Prevalence of Cerebrotendinous Xanthomatosis among Patients Diagnosed with Acquired Juvenile-Onset Idiopathic Bilateral Cataracts. / Freedman, Sharon F.; Brennand, Charlotte; Chiang, John; Debarber, Andrea; Del Monte, Monte A.; Duell, P. Barton; Fiorito, John; Marshall, Randall.

In: JAMA ophthalmology, 01.01.2019.

Research output: Contribution to journalArticle

Freedman, Sharon F. ; Brennand, Charlotte ; Chiang, John ; Debarber, Andrea ; Del Monte, Monte A. ; Duell, P. Barton ; Fiorito, John ; Marshall, Randall. / Prevalence of Cerebrotendinous Xanthomatosis among Patients Diagnosed with Acquired Juvenile-Onset Idiopathic Bilateral Cataracts. In: JAMA ophthalmology. 2019.
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title = "Prevalence of Cerebrotendinous Xanthomatosis among Patients Diagnosed with Acquired Juvenile-Onset Idiopathic Bilateral Cataracts",
abstract = "Importance: Cerebrotendinous xanthomatosis (CTX) is a rare autosomal recessive bile acid synthesis disorder caused by mutations in CYP27A1, the gene encoding sterol 27-hydroxylase, which results in elevated levels of plasma cholestanol and urinary bile alcohols. Clinical symptoms and signs may include early-onset chronic diarrhea, juvenile-onset bilateral cataracts, cholestatic jaundice, tendon xanthomas, and progressive neurological deterioration. Although initiation of treatment at a young age can prevent disease complications, diagnosis often occurs after the onset of permanent neurologic damage. Strategies are needed to facilitate early diagnosis. Objective: To evaluate the prevalence of CTX in a patient population diagnosed with early-onset idiopathic bilateral cataracts. Design, Setting, and Participants: This interim analysis of the Cerebrotendinous Xanthomatosis Prevalence Study was conducted in 26 active US sites from November 2015 to June 2017. The study included patients diagnosed as having idiopathic bilateral cataracts from ages 2 to 21 years. Potentially eligible study participants were identified through retrospective medical record review or on receiving care for cataracts at an active site. Data were analyzed from July 2017 to October 2018. Main Outcomes and Measures: Measurement of plasma cholestanol levels and optional urine bile alcohol screening were performed. A plasma cholestanol concentration of 0.4 mg/dL or greater or a positive urine bile alcohol result prompted CYP27A1 genetic testing to confirm the diagnosis of CTX. Results: Of 170 tested patients, 88 (51.8{\%}) were male, and the median (range) age was 10 (2-49) years. A total of 3 patients (1.8{\%}) had biochemical and genetic confirmation of newly diagnosed CTX (plasma cholestanol level greater than 1.0 mg/dL, positive urine bile alcohol result, and disease-causative mutations in CYP27A1). The mean (range) age at cataract diagnosis for patients with CTX was 12 (8-16) years. Reported symptoms included abnormal gait or balance (n = 3), learning disability (n = 2), cognitive decline (n = 2), seizures (n = 2), frequent bone fractures (n = 2), and chronic diarrhea (n = 1). Conclusions and Relevance: To date, 1.8{\%} of patients in this study were diagnosed as having CTX, which is approximately 500-fold the currently estimated prevalence of CTX in the general population (3 to 5 per 100000). These data suggest that juvenile-onset idiopathic bilateral cataracts may be useful as a screening marker for CTX and that ophthalmologists can play an important role in facilitating early identification of this condition..",
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AU - Freedman, Sharon F.

AU - Brennand, Charlotte

AU - Chiang, John

AU - Debarber, Andrea

AU - Del Monte, Monte A.

AU - Duell, P. Barton

AU - Fiorito, John

AU - Marshall, Randall

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N2 - Importance: Cerebrotendinous xanthomatosis (CTX) is a rare autosomal recessive bile acid synthesis disorder caused by mutations in CYP27A1, the gene encoding sterol 27-hydroxylase, which results in elevated levels of plasma cholestanol and urinary bile alcohols. Clinical symptoms and signs may include early-onset chronic diarrhea, juvenile-onset bilateral cataracts, cholestatic jaundice, tendon xanthomas, and progressive neurological deterioration. Although initiation of treatment at a young age can prevent disease complications, diagnosis often occurs after the onset of permanent neurologic damage. Strategies are needed to facilitate early diagnosis. Objective: To evaluate the prevalence of CTX in a patient population diagnosed with early-onset idiopathic bilateral cataracts. Design, Setting, and Participants: This interim analysis of the Cerebrotendinous Xanthomatosis Prevalence Study was conducted in 26 active US sites from November 2015 to June 2017. The study included patients diagnosed as having idiopathic bilateral cataracts from ages 2 to 21 years. Potentially eligible study participants were identified through retrospective medical record review or on receiving care for cataracts at an active site. Data were analyzed from July 2017 to October 2018. Main Outcomes and Measures: Measurement of plasma cholestanol levels and optional urine bile alcohol screening were performed. A plasma cholestanol concentration of 0.4 mg/dL or greater or a positive urine bile alcohol result prompted CYP27A1 genetic testing to confirm the diagnosis of CTX. Results: Of 170 tested patients, 88 (51.8%) were male, and the median (range) age was 10 (2-49) years. A total of 3 patients (1.8%) had biochemical and genetic confirmation of newly diagnosed CTX (plasma cholestanol level greater than 1.0 mg/dL, positive urine bile alcohol result, and disease-causative mutations in CYP27A1). The mean (range) age at cataract diagnosis for patients with CTX was 12 (8-16) years. Reported symptoms included abnormal gait or balance (n = 3), learning disability (n = 2), cognitive decline (n = 2), seizures (n = 2), frequent bone fractures (n = 2), and chronic diarrhea (n = 1). Conclusions and Relevance: To date, 1.8% of patients in this study were diagnosed as having CTX, which is approximately 500-fold the currently estimated prevalence of CTX in the general population (3 to 5 per 100000). These data suggest that juvenile-onset idiopathic bilateral cataracts may be useful as a screening marker for CTX and that ophthalmologists can play an important role in facilitating early identification of this condition..

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